The p53 tumor suppressor responds to a variety of stresses and initiates cell cycle arrest, apoptosis, or cellular senescence programs. One half of all human tumors have mutations in the p53 gene and more than 80% of tumors have defects in p53 signaling. A number of in vitro studies have shown that p53 can mediate a cellular senescence phenotype in various contexts. Moreover, some mouse models that exhibit abnormal longevity and aging phenotypes have altered p53 signaling, suggesting that p53 may affect organismal aging. The mechanisms through which p53 might affect the aging process remain unclear. To better understand the role of p53 in cancer suppression, our laboratory has generated a number of p53 mutant mouse models. Historically, p53 mutant mice have been highly susceptible to early cancers. Recently, however, we developed a new line of p53 mutant mice that showed unexpected phenotypes. Instead of cancer susceptibility, this line of mutant mice showed resistance to spontaneous cancers. In addition, these mice exhibited early appearance of a number of aging-associated phenotypes, including reduced longevity, muscle and skin atrophy, osteoporosis, and reduced stress tolerance. Current preliminary data indicates that this particular mutant allele of p53 encodes a truncated p53 that hyperactivates the wild type form of p53. Thus, these mutant mice may have a hyperactive p53 response. The goals of this proposal are to use this early aging mouse line and earlier p53 cancer susceptible mouse lines to show that (1) p53 does play an important role in organismal aging, and (2) determine some of the molecular and biological mechanisms through which p53 may influence the aging process.
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